Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Isolated fat cells derived from 10-wk-old Zucker obese rats utilized substantially greater amounts of glucose per cell in the presence or absence of insulin than those from lean rats. Initial rates of deoxyglucose or 3-0-methylglucose uptake in fat cells from Zucker obese rats were also 5--10 times greater than those observed in cells from lean rats. However, while 240 microU/ml insulin elicited a maximal response in fat cells from lean rats, this dose of hormone was only about 50% as effective as 24 microU/ml insulin in stimulating glucose metabolism or hexose transport in obese rat cells. This apparent rightward shift in the dose response-relationship could not be adequately explained on the basis of decreased insulin receptors since (125I-) insulin binding per fat cell was increased 2.5--3-fold in obesity, while receptor density on the cell surface in obesity was decreased only slightly. Soleus muscles from obese Zucker rats exhibited decreased basal rates of D(5-3H)glucose conversion to glycogen and H2O compared to those of lean controls. While the percent increase in glucose metabolism due to a supermaximal dose of insulin was similar in soleus muscles of lean and obese Zucker rats, a blunted response to a submaximal insulin dose was observed in muscles from the latter animals. This rightward shift in the dose-response relationship was also observed when deoxyglucose uptake was monitored in soleus muscles from obese rats. Binding of (1251-) insulin to soleus muscles at a medium concentration of 57 microU/ml was significantly decreased in obese compared to lean rats. We conclude that (1) fat cells do not contribute to the insulin resistance of 10-wk obese Zucer rats since glucose utilization is higher in these cells at all concentrations of insulin tested, (2) obese Zucker rat soleus muscle metabolism is defective in two respects--imparied basal glucose utilization and a rightward shift in the insulin dose-response relationship with respect to hexose transport, and (3) this latter defect involving decreased sensitivity of muscle to insulin appears to result from a marked decrease in cell surface receptors for the hormone.
 ...
PMID:Insulin response in skeletal muscle and fat cells of the genetically obese Zucker rat. 72 45

The purpose of this study was to investigate the pathophysiology of the intestinal microflora in the mechanism of fat deposition in hypothalamic obese (VMH) rats. Enterococci of VMH rats decreased 2 weeks after bilateral lesions in the ventromedial hypothalamic nuclei, and significantly decreased at 12 weeks after the lesions were made (P less than 0.01). Lactobacilli increased after 1 week after the lesions. Numbers of enterococci were negatively correlated with fat deposition in the parametrium (P less than 0.01), retroperitoneum (P less than 0.01), and liver (P less than 0.05), and also with Lee's index (P less than 0.02). Lactobacilli were positively correlated with serum glucose (P less than 0.01), fat deposition in the parametrium (P less than 0.02), and Lee's index (P less than 0.05). Enterococci probably decrease the intestinal absorption of cholesterol, and lactobacilli facilitate the absorption of hexose in the intestine, so a decrease in enterococci and increase in lactobacilli caused by hypothalamic lesions may accelerate the pathogenesis of obesity in VMH rats.
 ...
PMID:Relationship of fat deposition and intestinal microflora in VMH rats. 338 56

The effect of tolazamide (TZ), a sulfonylurea, on 14C-2-deoxyglucose (14C-2DG) tissue distribution and insulin levels of normal and obese mice was investigated using an in vivo physiological method. Acute doses of TZ (50 mg/kg ip) increased 14C-2DG levels in gastrocnemius muscle and retroperitoneal fat and produced a transient elevation of insulin which most likely accounts for the increased 14C-2DG levels in muscle and fat. The results demonstrate that the in vivo 14C-2DG method produced results consistent with known actions of sulfonylureas on in vitro hexose assimilation in muscle and fat. Subchronic treatment (7 days) with TZ 50 mg/kg ip twice daily did not result in increased insulin-stimulated 14C-2DG tissue levels in normal mice when compared to saline treated controls. However, insulin levels were lower in mice treated subchronically with TZ compared to saline controls suggesting an enhancement of insulin action. Viable yellow obese mice represent a model of maturity onset obesity presenting with insulin resistance. The insulin resistance of this obese strain appears to reside in the fat tissue as assessed by comparing 14C-2DG tissue levels of obese mice with lean littermate controls. Subchronic TZ treatment had no effect on 14C-2DG uptake in fat or muscle tissue of viable yellow obese mice and did not alter their plasma insulin levels. It appears that genetically obese viable yellow mice may be resistant to subchronic treatment with TZ.
 ...
PMID:2-Deoxyglucose tissue levels and insulin levels following tolazamide dosing in normal and obese mice. 353 34

It has been suggested that a decrease in the availability of oxygen to certain tissues may lead to increased metabolism of glucose through the hexose monophosphate shunt pathway and to increased synthesis of polyols, in particular myoinositol. It is further suggested that these "cytosolic reactions" result in stimulation of the phosphatidylinositol cycle by increasing substrate availability (i.e. phosphatidate, diglyceride and inositol). A relative decrease in local oxygen availability may therefore play a role in cell proliferation and differentiation and in the etiology of cancer, diabetic sequelae and obesity.
 ...
PMID:The role of oxygen deficiency and cytosolic reactions in cell growth. 364 Oct 33

Insulin rapidly represses expression of the gene encoding the insulin-responsive glucose transporter (GLUT4) in 3T3-L1 mouse adipocytes. Upon exposure to the hormone the cellular level of GLUT4 mRNA falls (t1/2 approximately 2.5 hr) to 20-30% of its initial level within 10 hr. This is followed by a similar decrease in the level of GLUT4 protein. Down-regulation of GLUT4 mRNA is a result of both rapid repression of transcription of the GLUT4 gene and an increased rate of turnover of the GLUT4 message. As a consequence of prolonged exposure to insulin, 3T3-L1 adipocytes lose their capacity for acute stimulation of hexose uptake by insulin. These findings provide an explanation for the resistance of glucose uptake to insulin in adipose tissue observed in non-insulin-dependent (type 2) diabetes mellitus, particularly that associated with hyperinsulinemia and obesity.
 ...
PMID:Insulin down-regulates expression of the insulin-responsive glucose transporter (GLUT4) gene: effects on transcription and mRNA turnover. 842 83

Why is it important to understand the mechanisms controlling intestinal adaptation? There are two major answers to this question. Firstly, in establishing the cellular and molecular events associated with intestinal adaptation, we will formulate a general framework that may be applied to the understanding of adaptation of other cell membranes. For example, alterations in the synthesis of glucose carriers and their subsequent insertion into membranes may alter sugar entry across the intestinal brush border membrane (BBM) using the sodium-dependent D-glucose transporter, SGLT1, or the BBM sodium-independent facultative fructose transporter, GLUT5, and may alter facilitated sugar exit across the basolateral membrane (BLM) using GLUT2. The precise role of transcriptional and translational processes in the up- or down-regulation of sugar transport requires further definition. Alterations in enterocyte microsomal lipid metabolic enzyme expression occurring during the course of intestinal adaptation will direct the synthesis of lipids destined for trafficking to the BBM and BLM domains of the enterocyte. This will subsequently alter the passive permeability properties of these membranes and ultimately influence lipid absorption. Therefore, establishing the physiological, cellular and molecular mechanisms of adaptation in the intestine will define principles that may be applied to other epithelia. Secondly, enterocyte membrane adaptation is subject to dietary modification, and these may be exploited as a means to enhance a beneficial or to reduce a detrimental aspect of the intestinal adaptive process in disease states. Alterations in membrane function occur in association with changes in dietary lipids, and these are observed in a variety of cells and tissues including lymphocytes, testes, liver, adipocytes, nerve tissue, nuclear envelope and mitochondria. Therefore, the elucidation of the mechanisms of intestinal adaptation and the manner whereby dietary manipulation modulates these processes affords the future possibility of dietary engineering aimed at using food as a therapeutic agent. It is hoped this approach will form the centerpiece for future investigation that would focus on disease prevention, as well as on the development of better therapeutic strategies to prevent the development or to treat the complications of conditions such as diabetes mellitus, obesity, hyperlipidemia and inflammatory bowel diseases. This review deals with the physiology of glucose transport with specific emphasis on transporters of the brush border membrane (BBM) and the basolateral membrane (BLM). On the BBM the sodium (Na)/glucose transporters (SGLT1 and SGLT2), the Na-independent transporter (GLUT5), and on the BLM the hexose transporter (GLUT2) are discussed. The molecular biology of these transporters is also reviewed.
 ...
PMID:Adaptation of intestinal nutrient transport in health and disease. Part I. 907 26

Serum mannose concentration increases in diabetic patients and correlates closely with blood glucose. In patients with glomerulonephritis, serum mannose and mannose/glucose ratio positively correlate with dyslipidemia and the extent of urinary protein excretion. We investigated whether changes in serum mannose mark subjects with features of metabolic syndrome, including obesity, hypertension, glucose intolerance, and dyslipidemia. The study comprised 20 patients with mean age of 68 (SD 11) years, body mass index 27.2 (SD 5.1) kg/m2, blood glucose 6.2 (SD 1.6) mmol/L, serum total cholesterol 6.3 (SD 1.2) mmol/L, triglyceride 2.0 (SD 0.08) mmol/L, uric acid 320 (SD 109) micromol/L, mannose 60.0 (SD 17) micromol/L, and mannose/glucose ratio 9.7 (SD 1.8) micromol/mmol. Serum mannose correlated with blood glucose (r=0.758, p=0.012), triglyceride (r=0.478, p=0.023), and HDL-cholesterol (r = approximately 0.427, p=0.022). Mannose/glucose ratio correlated with BMI (r=0.581, p=0.033), mannose (r=0.491, p=0.035), and uric acid (r=0.608, p=0.027). The rate of VLDL lipoprotein turnover may be instrumental in the regulation of serum mannose concentration. We conclude that an altered mannose metabolism is a novel consideration among the metabolic abnormalities in the metabolic syndrome.
 ...
PMID:Metabolic syndrome is associated with changes in D-mannose metabolism. 1069 Oct 51

D-glucose was previously reported to cause a concentration-related decrease in the 36Cl- content of prelabeled islets prepared from ob/ob mice, a current animal model of inherited obesity. From these findings, it was inferred that the hexose stimulates Cl- efflux from islet cells and that such an increase in Cl- permeability may partly mediate glucose-induced depolarization of insulin-producing cells. The aim of the present study was to investigate the possible extension of these findings to islets prepared from normal rats by measuring the changes evoked by increasing concentrations of D-glucose in 36Cl- outflow itself from prelabeled isolated islets. After 60 min preincubation at 37 degrees C in the presence of 3 mM D-glucose and 36Cl- (75 microCi/mL), the islets were incubated for 8-10 min at 37 degrees C in the presence of increasing concentrations of the hexose (3-20 mM). The changes in 36Cl- outflow during incubation indicated that D-glucose, in excess of a threshold concentration close to 5 mM, indeed increases effluent radioactivity from the prelabeled islets. It is proposed, therefore, that a gating of volume-sensitive anion channels in glucose-stimulated insulin-producing islet cells participates in the depolarization of the plasma membrane recorded in the range of insulinotropic concentrations of the hexose.
 ...
PMID:Stimulation by D-glucose of 36Cl- efflux from prelabeled rat pancreatic islets. 1554 2

Adipose tissue modulates whole body metabolism and insulin sensitivity by controlling circulating lipid levels and producing molecules that can regulate fatty acid metabolism in such tissues as muscle and liver. We have developed RNA interference (RNAi) screens to identify genes in cultured adipocytes that regulate insulin signalling and key metabolic pathways. These short interfering RNA (siRNA)-based screens identified the transcriptional corepressor receptor interacting protein 140 (RIP140) (J Clin Invest 116: 125, 2006) and the mitogen-activated protein kinase (MAP4k4) (Proc Natl Acad Sci USA 103: 2087, 2006) as negative regulators of insulin-responsive hexose uptake and oxidative metabolism. Gene expression profiling revealed that RIP140 depletion upregulates the expression of clusters of genes in the pathways of glucose uptake, glycolysis, tricarboxylic acid cycle, fatty acid oxidation, mitochondrial biogenesis and oxidative phosphorylation. RIP140-null mice resist weight gain on a high-fat diet and display enhanced glucose tolerance. MAP4k4 depletion in adipocytes increases many of the RIP140-sensitive genes, increases adipogenesis and mediates some actions of tumour necrosis factor-alpha (TNF-alpha). Remarkably, another hit in our RNAi screens was fat specific protein 27 (FSP27), a highly expressed isoform of Cidea. We discovered that FSP27 unexpectedly associates specifically with lipid droplets and regulates fat storage. We conclude that RIP140, MAP4k4 and the novel lipid droplet protein FSP27 are powerful regulators of adipose tissue metabolism and are potential therapeutic targets for controlling metabolic disease. The discovery of these novel proteins validates the power of RNAi screening for discovery of new therapeutic approaches to type 2 diabetes and obesity.
 ...
PMID:RNAi screens reveal novel metabolic regulators: RIP140, MAP4k4 and the lipid droplet associated fat specific protein (FSP) 27. 1817 33

Excess carbohydrate intake leads to fat accumulation and insulin resistance. Glucose and insulin coordinately regulate de novo lipogenesis from glucose in the liver, and insulin activates several transcription factors including SREBP1c and LXR, while those activated by glucose remain unknown. Recently, a carbohydrate response element binding protein (ChREBP), which binds to the carbohydrate response element (ChoRE) in the promoter of rat liver type pyruvate kinase (LPK), has been identified. The target genes of ChREBP are involved in glycolysis, lipogenesis, and gluconeogenesis. Although the regulation of ChREBP remains unknown in detail, the transactivity of ChREBP is partly regulated by a phosphorylation/dephosphorylation mechanism. During fasting, protein kinase A and AMP-activated protein kinase phosphorylate ChREBP and inactivate its transactivity. During feeding, xylulose-5-phosphate in the hexose monophosphate pathway activates protein phosphatase 2A, which dephosphorylates ChREBP and activates its transactivity. ChREBP controls 50% of hepatic lipogenesis by regulating glycolytic and lipogenic gene expression. In ChREBP (-/-) mice, liver triglyceride content is decreased and liver glycogen content is increased compared to wild-type mice. These results indicate that ChREBP can regulate metabolic gene expression to convert excess carbohydrate into triglyceride rather than glycogen. Furthermore, complete inhibition of ChREBP in ob/ob mice reduces the effects of the metabolic syndrome such as obesity, fatty liver, and glucose intolerance. Thus, further clarification of the physiological role of ChREBP may be useful in developing treatments for the metabolic syndrome.
 ...
PMID:ChREBP: a glucose-activated transcription factor involved in the development of metabolic syndrome. 1849 Aug 33


1 2 3 Next >>